Compositions for oral administration of zoledronic acid or related compounds for treating low back pain

ABSTRACT

Oral dosage forms of bisphosphonate compounds, such as zoledronic acid, can be used to treat or alleviate pain or related conditions. The oral bioavailability of zoledronic acid can be enhanced by administering the zoledronic acid in the disodium salt form.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/279,229, filed May 15, 2014, which is a continuation of U.S. patentapplication Ser. No. 14/063,979, filed Oct. 25, 2013, which is acontinuation-in-part of U.S. patent application Ser. No. 13/894,274,filed May 14, 2013, which embodiments the benefit of U.S. ProvisionalApplications 61/646,538, filed May 14, 2012; 61/647,478, filed May 15,2012; 61/654,292, filed Jun. 1, 2012; 61/654,383, filed Jun. 1, 2012;61/655,527, filed Jun. 5, 2012; 61/655,541, filed Jun. 5, 2012;61/764,563, filed Feb. 14, 2013; 61/762,225, filed Feb. 7, 2013;61/767,647, filed Feb. 21, 2013; 61/767,676, filed Feb. 21, 2013; and61/803,721, filed Mar. 20, 2013, all of which are incorporated byreference in their entirety herein.

BACKGROUND

Bisphosphonate compounds are potent inhibitors of osteoclast activity,and are used clinically to treat bone-related conditions such asosteoporosis and Paget's disease of bone; and cancer-related conditionsincluding multiple myeloma, and bone metastases from solid tumors. Theygenerally have low oral bioavailability.

SUMMARY

It has been discovered that oral dosage forms of bisphosphonatecompounds, such as zoledronic acid, can be used to treat or alleviatepain or related conditions.

Some embodiments include a method of enhancing the oral bioavailabilityof zoledronic acid comprising orally administering a dosage formcontaining zoledronic acid in the disodium salt form.

Some embodiments include a dosage form comprising zoledronic acid in thedisodium salt form, wherein the bioavailability, in a mammal, ofzoledronic acid in the disodium salt form is greater than thebioavailability of zoledronic acid in the diacid form would be in thesame dosage form.

Some embodiments include a dosage form comprising zoledronic acid in thedisodium salt form, wherein the dosage form contains an amount ofzoledronic acid in the disodium salt form that provides an area underthe plasma concentration curve of zoledronic acid of about 4 ng·h/mL toabout 2000 ng·h/mL to a human being to which the dosage form isadministered.

Some embodiments include a dosage form comprising zoledronic acid in thedisodium salt form, wherein the disodium salt form is present in a lowermolar amount than would be present if the zoledronic acid were in thediacid form; and wherein the zoledronic acid in the disodium salt formhas an improved bioavailability as compared to the zoledronic acid inthe diacid form to the extent that the lower molar amount of thedisodium salt in the dosage form does not reduce the amount ofzoledronic acid delivered to the plasma of a mammal.

Although an oral dosage form with enhanced bioavailability with respectto the bisphosphonate compound can be used, the treatment can also beeffective using an oral dosage form that includes a bisphosphonatecompound, such as zoledronic acid, wherein the bioavailability of thebisphosphonate is unenhanced, or is substantially unenhanced.

Some embodiments include a method of relieving inflammatory paincomprising administering an oral dosage form containing zoledronic acidto a mammal in need thereof, wherein the mammal experiences significantpain relief more than 3 hours after administration of the dosage form.

Some embodiments include a method of relieving pain associated with anarthritis comprising administering an oral dosage form containingzoledronic acid to a human being in need thereof.

Some embodiments include a method of treating complex regional painsyndrome comprising administering an oral dosage form containingzoledronic acid to a mammal in need thereof.

Some embodiments include an oral dosage form comprising zoledronic acid,wherein the oral bioavailability of zoledronic acid is substantiallyunenhanced. For example, in some embodiments, the oral bioavailabilityin the dosage form is about 0.01% to about 4%.

Some embodiments include a pharmaceutical product comprising more thanone unit of an oral dosage form described herein. In some embodiments,each unit of the oral dosage form contains about 1 mg to about 50 mg ofzoledronic acid.

Some embodiments include a method of relieving inflammatory paincomprising administering an oral dosage form containing zoledronic acidto a mammal in need thereof.

In some embodiments, the mammal receives a total monthly dose ofzoledronic acid that is about 800 mg/m² or less.

In some embodiments, the dosage form contains about 10 mg/m² to about 20mg/m² based upon the body surface area of the mammal.

Some embodiments include a method of relieving inflammatory paincomprising orally administering zoledronic acid to a mammal in needthereof.

In some embodiments, about 300 mg/m² to about 600 mg/m² of zoledronicacid is administered per month, based upon the body surface area of themammal.

In some embodiments, about 50 mg/m² to about 600 mg/m² of zoledronicacid is administered per month, based upon the body surface area of themammal.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a plot of pain compression thresholds in a rat model ofinflammatory pain using three different doses of zoledronic acid.Measurements were taken at baseline (BL) and at various time pointsafter dosing on the days indicated.

FIG. 2A is a graph depicting reversal of arthritis pain for twodifferent doses of zoledronic acid in a rat model of arthritis pain.

FIG. 2B is a graph depicting pain thresholds for two different doses ofzoledronic acid in a rat model of arthritis pain.

FIG. 3 is a graph summarizing the results for vehicle and zoledronicacid treated rats in a rat model of complex regional pain syndrome.

FIG. 4 depicts hindpaw pain thresholds for vehicle and zoledronic acidtreated rats in a rat model of complex regional pain syndrome.

FIG. 5 depicts weight bearing for vehicle and zoledronic acid treatedrats in a rat model of complex regional pain syndrome.

FIG. 6 depicts paw thickness change for vehicle and zoledronic acidtreated rats in a rat model of complex regional pain syndrome.

FIG. 7 depicts the aqueous solubility of disodium zoledronatetetrahydrate as compared to the diacid form of zoledronic acid.

FIG. 8 depicts the plasma concentration of zoledronic acid in dogs overtime after administration of 150 mg of the disodium salt form ofzoledronic acid and the diacid form of zoledronic acid.

FIG. 9 depicts the compressibility of dosage forms containing zoledronicacid in the disodium salt form as compared to the diacid form.

DETAILED DESCRIPTION

Bisphosphonate compounds such as pamidronate or pamidronic acid,neridronate or neridronic acid, olpadronate or olpadronic acid,alendronate or alendronic acid, incadronate or incadronic acid,ibandronate or ibandronic acid, risedronate or risedronic acid,zoledronate or zoledronic acid, etidronate or etidronic acid, clodronateor clodronic acid, tiludronate or tiludronic acid, etc., may be used fora number of medical purposes, such as treatment of undesirableconditions or diseases, including pain relief. This may be accomplishedin many instances by administration of oral dosage forms. Generally, anoral dosage form comprising a bisphosphonate such as zoledronic acid isadministered orally to a mammal, such as a human being, at least once,to treat a disease or condition, or to relieve pain.

The term “treating” or “treatment” broadly includes any kind oftreatment activity, including the diagnosis, cure, mitigation, orprevention of disease in man or other animals, or any activity thatotherwise affects the structure or any function of the body of man orother animals.

An oral dosage form of a bisphosphonate such as zoledronic acid may beused to treat, or provide relief of, any type of pain including, but notlimited to, inflammatory pain, arthritis pain, complex regional painsyndrome, lumbosacral pain, musculoskeletal pain, neuropathic pain,chronic pain, cancer-related pain, acute pain, postoperative pain, etc.In some instances, pain relief may be palliative, or pain relief may beprovided independent of improvement of the disease or condition or theunderlying cause of the disease or condition. For example, although theunderlying disease may not improve, or may continue to progress, anindividual suffering from the disease may experience pain relief. Insome embodiments, enhanced bioavailability of the zoledronic acid may beachieved in treating one of these conditions by administering a dosageform comprising zoledronic acid in the form of a disodium salt. This mayallow a reduced molar amount of the disodium salt to be used as comparedto what would be used with the diacid form.

In some embodiments, the mammal being treated is not suffering from bonemetastasis. In some embodiments, the mammal being treated is notsuffering from cancer. In some embodiments, the mammal being treated isnot suffering from osteoporosis.

For example, zoledronic acid or another bisphosphonate may beadministered orally to relieve musculoskeletal pain including low backpain, and pain associated with rheumatoid arthritis, juvenile rheumatoidarthritis, osteoarthritis, erosive osteoarthritis, sero-negative(non-rheumatoid) arthropathies, non-articular rheumatism, peri-articulardisorders, axial spondyloarthritis including ankylosing spondylitis,Paget's disease, fibrous dysplasia, SAPHO syndrome, transientosteoarthritis of the hip, vertebral crush fractures, osteoporosis, etc.In some embodiments, enhanced bioavailability of the zoledronic acid maybe achieved in treating one of these conditions by administering adosage form comprising zoledronic acid in the form of a disodium salt.This may allow a reduced molar amount of the disodium salt to be used ascompared to what would be used with the diacid form.

In some embodiments, zoledronic acid or another bisphosphonate may alsobe administered orally to relieve neuropathic pain, including diabeticperipheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia,monoradiculopathies, phantom limb pain, and central pain. Other causesof neuropathic pain include cancer-related pain, lumbar nerve rootcompression, spinal cord injury, post-stroke pain, central multiplesclerosis pain, HIV-associated neuropathy, and radio-therapy orchemo-therapy associated neuropathy. In some embodiments, enhancedbioavailability of the zoledronic acid may be achieved in treating oneof these conditions by administering a dosage form comprising zoledronicacid in the form of a disodium salt. This may allow a reduced molaramount of the disodium salt to be used as compared to what would be usedwith the diacid form.

In some embodiments, zoledronic acid or another bisphosphonate may beadministered orally to relieve inflammatory pain includingmusculoskeletal pain, arthritis pain, and complex regional painsyndrome. In some embodiments, enhanced bioavailability of thezoledronic acid may be achieved in treating one of these conditions byadministering a dosage form comprising zoledronic acid in the form of adisodium salt. This may allow a reduced molar amount of the disodiumsalt to be used as compared to what would be used with the diacid form.

Examples of musculoskeletal pain include low back pain; and painassociated with vertebral crush fractures, fibrous dysplasia,osteogenesis imperfecta, Paget's disease of bone, transientosteoporosis, and transient osteoporosis of the hip.

Arthritis refers to inflammatory joint diseases that can be associatedwith pain. Examples of arthritis pain include pain associated withosteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenilerheumatoid arthritis, sero-negative (non-rheumatoid) arthropathies,non-articular rheumatism, peri-articular disorders, neuropathicarthropathies including Charcot's foot, axial spondyloarthritisincluding ankylosing spondylitis, and SAPHO syndrome.

In some embodiments, a human being that is treated for arthritis by anoral dosage form of zoledronic acid has an age of about 10 years toabout 90 years, about 20 years to about 80 years, about 30 years toabout 75 years old, about 40 years to about 70 years, about 1 year toabout 16 years, or about 80 years to about 95 years.

In some embodiments, a human being that is treated for arthritis by anoral dosage form of zoledronic acid has suffered from the arthritis forat least 1 month, at least 2 months, at least 6 months, or at least 1year.

In some embodiments, the arthritis affects, a knee, an elbow, a wrist, ashoulder, or a hip.

In some embodiments, zoledronic acid or another bisphosphonate may beadministered orally to relieve complex regional pain syndrome, such ascomplex regional pain syndrome type I (CRPS-I), complex regional painsyndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is atype of inflammatory pain. CRPS can also have a neuropathic component.

Complex regional pain syndrome is a debilitating pain syndrome. It ischaracterized by severe pain in a limb accompanied by edema, andautonomic, motor and sensory changes.

With respect to use of oral zoledronic acid for relieving painassociated with an inflammatory condition, relief of pain can beshort-term, e.g. for a period of hours after administration of thedosage form, and/or relief of pain can be long-term, e.g. lasting fordays, weeks, or even months after oral administration of zoledronicacid. In some embodiments, a mammal, such as a human being, experiencessignificant pain relief at least about 3 hours, at least about 6 hours,at least about 12 hours, at least about 24 hours, at least about 48hours, at least about one week, at least about 2 weeks, or at leastabout 3 weeks after administration of an oral dosage form comprisingzoledronic acid. In some embodiments, a mammal, such as a human being,experiences significant pain relief during at least part of the timefrom about 3 hours to about 2 weeks, about 3 hours to about 3 weeks,about 3 hours to about 24 hours, about 6 hours to about 2 weeks, orabout 6 hours to about 24 hours, about 3 days to about 2 weeks, about 6days to about 2 weeks, after administration of an oral dosage formcomprising zoledronic acid.

With respect to the treatment of any condition recited herein, in someembodiments a first oral dosage form comprising zoledronic acid isadministered and a second oral dosage form comprising oral zoledronicacid is administered. The timing of the administration of the two dosageforms may be such that, with respect to the first oral dosage form, thesecond oral dosage with respect to the first oral dosage form, thesecond oral dosage form is administered at 5×T_(max) or greater (e.g.,if T_(max) is 1 hour, at 5 hours or later), at least 10×T_(max) orgreater, at least about 15×T_(max) or greater, at least about 20×T_(max)or greater, at least about 50×T_(max) or greater, or at least about200×T_(max) or greater, wherein T_(max) is the time of maximum plasmaconcentration for the first oral dosage form.

Some embodiments include treatment of a condition recited herein, suchas inflammatory pain, arthritis, or complex regional pain syndrome,wherein the treatment comprises either: administering only one dosageform to a mammal to treat the condition, or administering a first dosageform to the mammal, followed by administering a second dosage form tothe mammal. If two or more dosage forms are administered, the secondoral dosage form is administered before the maximum pain relievingeffect of the first oral dosage form is achieved, or before a peak inthe pain relieving effect of the first oral dosage form is experiencedby a mammal, receiving the dosage form. In some embodiments, the secondoral dosage form is administered before an observable pain relievingeffect is achieved. In some embodiments, the second dosage form isadministered about 12 hours to about 60 days, about 24 hours to about 28days, about 24 hours to about 7 days, about 24 hours to about 14 days,or about 24 hours to about 21 days, after the first dosage form isadministered.

Some embodiments include treatment of a condition recited herein, suchas inflammatory pain, arthritis, or complex regional pain syndrome,wherein the treatment comprises administering a first dosage form to themammal, followed by administering a second dosage form to the mammal,wherein the second dosage form is administered after the maximum painrelieving effect of the first oral dosage form is achieved, and thesecond oral dosage form is administered while the mammal is stillexperiencing pain relief from the first oral dosage form, or while thepain relieving effect from the first oral dosage form is observable. Insome embodiments, the second dosage form is administered about 12 hoursto about 60 days, about 24 hours to about 28 days, about 24 hours toabout 7 days, about 24 hours to about 14 days, or about 24 hours toabout 21 days, after the first dosage form is administered.

Zoledronic acid or another bisphosphonate may also be administeredorally to relieve cancer-related pain, including pain associated withmultiple myeloma and bone metastases from solid tumors. In someembodiments, zoledronic acid is used to treat pain that is notcancer-related pain. For example, zoledronic acid may be used to treatpain that is not associated with multiple myeloma, bone metastasis fromsolid tumors, hypercalcemia of malignancy, giant cell tumor of bone,blood cancers or leukemias, or solid tumors or cancers. In someembodiments, enhanced bioavailability of the zoledronic acid may beachieved in treating one of these conditions by administering a dosageform comprising zoledronic acid in the form of a disodium salt. This mayallow a reduced molar amount of the disodium salt to be used as comparedto what would be used with the diacid form.

In addition to relieving pain, oral administration of zoledronic acid oranother bisphosphonate may also be useful to treat diseases orconditions that may or may not include a pain component. For example,zoledronic acid or another bisphosphonate may be useful to treat any ofthe pain conditions or types of conditions listed above, includingtreatment that does not simply relieve the pain of those conditions, andtreatment that is carried out in such a way that the condition istreated without pain relief occurring. In addition to any pain reliefzoledronic acid or another bisphosphonate may or may not provide,zoledronic acid or another bisphosphonates may be used to treat adisease or condition such as a metabolic disease or condition; aninflammatory disease or condition, including an inflammatory disease orcondition that is not associated with pain; a cancer disease orcondition; a neurological disease or condition; etc. In someembodiments, enhanced bioavailability of the zoledronic acid may beachieved in treating one of these conditions by administering a dosageform comprising zoledronic acid in the form of a disodium salt. This mayallow a reduced molar amount of the disodium salt to be used as comparedto what would be used with the diacid form.

In some embodiments, oral administration of zoledronic acid or anotherbisphosphonate may also be useful to treat complex regional painsyndrome, rheumatoid arthritis, osteoarthritis, erosive osteoarthritis,axial spondyloarthritis including ankylosing spondylitis, acutevertebral crush fracture, fibrous dysplasia, SAPHO syndrome,osteoporosis, transient osteoporosis, or transient osteoporosis of thehip. In some embodiments, enhanced bioavailability of the zoledronicacid may be achieved in treating one of these conditions byadministering a dosage form comprising zoledronic acid in the form of adisodium salt. This may allow a reduced molar amount of the disodiumsalt to be used as compared to what would be used with the diacid form.

In some embodiments, oral administration of zoledronic acid or anotherbisphosphonate may also be useful to treat hypercalcemia of malignancy,multiple myeloma, bone metastases from solid tumors, Paget's disease ofbone, giant cell tumor of bone, blood cancers or leukemias, or solidtumors or cancers. In some embodiments, enhanced bioavailability of thezoledronic acid may be achieved in treating one of these conditions byadministering a dosage form comprising zoledronic acid in the form of adisodium salt. This may allow a reduced molar amount of the disodiumsalt to be used as compared to what would be used with the diacid form.

Zoledronic acid has the structure shown below, and is also referred toas zoledronate.

Unless otherwise indicated, any reference to a compound herein, such aszoledronic acid, by structure, name, or any other means, includespharmaceutically acceptable salts, such as the disodium salt; alternatesolid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; orany other chemical species that may rapidly convert to a compounddescribed herein under conditions in which the compounds are used asdescribed herein.

In some embodiments, zoledronic acid is administered in a dosage formcomprising a salt form, such as a salt of a dianion of zoledronic acid.In some embodiments, zoledronic acid is administered in a dosage formcomprising a disodium salt form of zoledronic acid. In some embodiments,zoledronic acid is administered in a sodium salt form, such as amonosodium salt, a disodium salt, a trisodium salt, etc. In somecircumstances, use of the disodium salt may be desirable. For example,the disodium salt is much more soluble in water than the diacid form. Asa result, in some processes, the disodium salt can be easier to workwith than the diacid form. Additionally, the sodium salt may be morebioavailable and/or more rapidly absorbed when taken orally as comparedto the diacid form.

The oral bioavailability of zoledronic acid may be enhanced by orallyadministering the zoledronic acid in the disodium salt form. Forexample, the bioavailability of zoledronic acid may be improved by atleast about 10%, at least about 20%, at least about 30%, at least about50%, and/or up to about 100%, or up to about 200%, as compared toadministration of zoledronic acid in the diacid form.

Because of the improved bioavailability of the disodium salt a dosageform may contain, or a mammal, such as a human being, may receive, on amolar basis, less of the disodium salt form of zoledronic acid thanwould otherwise be administered of the diacid form of zoledronic acid.For example, a dosage form may contain, or a mammal may receive, atleast about 10 mole % less, at least about 20 mole % less, at leastabout 40 mole % less, at least about 50 mole % less, and/or up to about90 mole % less or 95 mole % less, of the disodium salt form as comparedthe amount of the diacid form of zoledronic acid that would otherwise beadministered, such as a molar amount that would be administered ofzoledronic acid in the diacid form in order to achieve the same plasmalevels of zoledronic acid.

In some embodiments, a dosage form contains, or a mammal (such as ahuman being) is administered, an amount of the disodium salt form, on amolar basis, that has a value of about 0.8 n_(d) to about 1.2 n_(d) orabout 0.9 n_(d) to about 1.1 n_(d), wherein:n _(d)=(b _(a) /b _(d))(n _(a))wherein b_(a) is the bioavailability of the diacid form, b_(d) is thebioavailability of the disodium salt form, and n_(a) is the number ofmoles of the diacid that would be administered in a dosage formcontaining the diacid form of zoledronic acid. For example, if thediacid form has a bioavailability (b_(a)) of 0.01 and the disodium saltform has a bioavailability (b_(d)) of 0.015, and a dosage form wouldnormally contain 0.001 moles of the diacid, n_(d) would be(0.01/0.015)(0.001 moles), or about 0.00067 moles. In some embodiments,the disodium salt is administered in an amount that has a value of aboutn_(d).

With respect to oral dosage forms comprising a reduced molar amount ofthe disodium salt of zoledronic acid as compared to the diacid form ofzoledronic acid, in some embodiments, the bioavailability of thezoledronic acid in the disodium salt form is sufficiently high that, ifthe drug is administered to a mammal, at least as much zoledronic acidis present in the blood of the mammal as would be present if zoledronicacid were administered in the diacid form.

With respect to oral dosage forms comprising the disodium salt form ofzoledronic acid, in some embodiments, the disodium salt form is presentin a lower molar amount than would be present if the zoledronic acidwere in the diacid form; and the zoledronic acid in the disodium saltform has an improved bioavailability as compared to the zoledronic acidin the diacid form to the extent that the lower molar amount of thedisodium salt in the dosage form does not reduce the amount ofzoledronic acid delivered to the plasma of a mammal.

In some embodiments, the zoledronic acid in the disodium salt form ispresent in an amount such that the oral dosage form provides an areaunder the plasma concentration curve of zoledronic acid of about 4ng·h/mL to about 2000 ng·h/mL to the mammal each time the zoledronicacid in the disodium salt is administered.

In some embodiments, the zoledronic acid in the disodium salt form ispresent in an amount such that the oral dosage form provides an areaunder the plasma concentration curve of zoledronic acid of about 100ng·h/mL to about 2000 ng·h/mL, about 100 ng·h/mL to about 1000 ng·h/mL,about 500 ng·h/mL to about 1000 ng·h/mL, or about 500 ng·h/mL to about700 ng·h/mL in the mammal to which the dosage form is administered. Thisamount may be suitable for administration of the oral dosage form aboutevery 3 to 4 weeks.

In some embodiments, the zoledronic acid in the disodium salt form ispresent in an amount such that the oral dosage form provides an areaunder the plasma concentration curve of zoledronic acid of about 20ng·h/mL to about 700 ng·h/mL, about 50 ng·h/mL to about 500 ng·h/mL, orabout 100 ng·h/mL to about 200 ng·h/mL, in the mammal to which thedosage form is administered. This amount may be suitable for weeklyadministration of the oral dosage, or for administration of 3 to 5individual dosages during a month. The individual dosages could be givenat regular intervals, given during the first week, or at any otherschedule that provides 3 to 5 dosages during the month.

In some embodiments, the zoledronic acid in the disodium salt form ispresent in an amount such that the oral dosage form provides an areaunder the plasma concentration curve of zoledronic acid of about 4ng·h/mL to about 100 ng·h/mL, about 10 ng·h/mL to about 50 ng·h/mL, orabout 10 ng·h/mL to about 30 ng·h/mL, in the mammal to which the dosageform is administered. This amount may be suitable for dailyadministration of the oral dosage form.

Oral administration of zoledronic acid, particularly oral administrationof the disodium salt form of zoledronic acid, can result in moresustained plasma levels of the drug as compared to parenteral modes ofadministration, such intravenous or subcutaneous. For example, theamount of zoledronic acid in the plasma can be significantly higher fororal administration of the disodium salt about 24 hours or 48 hours, orlonger, after administration. In some embodiments, oral zoledronic acidhas a 24 hour sustained plasma level factor of about 1 or higher, suchas about 1 to about 10, about 1 to about 5, about 3 to about 5, or about3 to about 4. In some embodiments, an orally administered dosage form ofzoledronic acid has a 24 hour sustained plasma level factor or a 48 hoursustained plasma level factor that is higher, such as at least 1.2times, at least about 2 times, at least about 5 times, about 1.2 timesto about 20 times, about 2 times to about 15 times, about 5 times toabout 10 times, or about 8 to about 15 times that of intravenouslyadministered zoledronic acid. A “sustained plasma level factor,” p_(f),is determined by the equation:p _(f)=1000(C _(t) /C _(max))wherein C_(max) is the maximum plasma concentration of zoledronic acidafter it is administered and C_(t) is the plasma concentration ofzoledronic acid at the time of interest, such as 24 hours. Forparenteral administration, the C_(max) can be about the C₀, or theconcentration right after injection of the entire amount of the druginto the body. Sustained plasma level factors can also be obtained forother times, such as 48 hours, by using the plasma concentration ofzoledronic acid for C_(t) in the equation above. For example, if themaximum plasma level of zoledronic acid after administration is 1000ng/mL and the plasma level of zoledronic acid at 24 hours is 1 ng/mL,the 24 hour sustained plasma level factor is 1.

In some embodiments, the disodium salt form of zoledronic acid providesan enhancement to bioavailability, as compared to the diacid form ofzoledronic acid, which adds to any enhancement to bioavailabilityprovided by any bioavailability-enhancing agents in the dosage form. Insome embodiments, the disodium salt form of zoledronic acid provides anenhancement to bioavailability, as compared to the diacid form ofzoledronic acid, which is greater than any enhancement tobioavailability provided by any bioavailability-enhancing agents in thedosage form. In some embodiments, the disodium salt form of zoledronicacid may be administered in a dosage form that is substantially free ofbioavailability-enhancing agents.

In some embodiments, a dosage form comprising a disodium salt ofzoledronic acid is a solid.

In some embodiments, a dosage form comprising a disodium salt ofzoledronic acid is used to treat an inflammatory condition.

In some embodiments, a dosage form comprising a disodium salt ofzoledronic acid is used to treat arthritis.

In some embodiments, a dosage form comprising a disodium salt ofzoledronic acid is used to treat complex regional pain syndrome.

In some embodiments, zoledronic acid is in a form that has an aqueoussolubility, meaning the solubility in water, greater than 1% (w/v),about 5% (w/v) to about 50% (w/v), about 5% (w/v) to about 20% (w/v),about 10% (w/v) to about 15% (w/v), or about 12% (w/v) to about 13%(w/v).

The disodium salt form of zoledronic acid can be more compressible thanthe diacid form of zoledronic acid. This can make it easier for a dosageform to have a desired hardness. It can also make it easier to increasethe drug load, so that a smaller tablet can be given for a given dosagestrength. In some embodiments, a solid dosage form of zoledronic acid,such as the diacid form of zoledronic acid or the disodium salt form ofzoledronic acid, can have a hardness of about 5 kPa to about 20 kPa orabout 5 kPa to about 14 kPa.

Zoledronic acid or another bisphosphonate may be combined with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice as described, forexample, in Remington's Pharmaceutical Sciences, 2005, the disclosure ofwhich is hereby incorporated herein by reference, in its entirety. Therelative proportions of active ingredient and carrier may be determined,for example, by the solubility and chemical nature of the compounds,chosen route of administration and standard pharmaceutical practice.

Zoledronic acid or another bisphosphonate may be administered by anymeans that may result in the contact of the active agent(s) with thedesired site or site(s) of action in the body of a patient. Thecompounds may be administered by any conventional means available foruse in conjunction with pharmaceuticals, either as individualtherapeutic agents or in a combination of therapeutic agents. Forexample, they may be administered as the sole active agents in apharmaceutical composition, or they can be used in combination withother therapeutically active ingredients.

Zoledronic acid or another bisphosphonate may be administered to a humanpatient in a variety of forms adapted to the chosen route ofadministration, e.g., orally, rectally, or parenterally. Parenteraladministration in this respect includes, but is not limited to,administration by the following routes: pulmonary, intrathecal,intravenous, intramuscular, subcutaneous, intraocular, intrasynovial,transepithelial including transdermal, sublingual and buccal; topically;nasal inhalation via insufflation; and rectal systemic.

The effective amount of zoledronic acid or another bisphosphonate willvary depending on various factors known to the treating physicians, suchas the severity of the condition to be treated, route of administration,formulation and dosage forms, physical characteristics of thebisphosphonate compound used, and age, weight and response of theindividual patients.

The amount of zoledronic acid or another bisphosphonate in a therapeuticcomposition may vary. For example, some liquid compositions may compriseabout 0.0001% (w/v) to about 50% (w/v), about 0.01% (w/v) to about 20%(w/v), about 0.01% to about 10% (w/v), about 0.001% (w/v) to about 1%(w/v), about 0.1% (w/v) to about 0.5% (w/v), about 1% (w/v) to about 3%(w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7%(w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15%(w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30%(w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about50% (w/v) of zoledronic acid.

Some solid compositions may comprise at least about 5% (w/w), at leastabout 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), atleast about 70% (w/w), at least about 80%, about 10% (w/w) to about 30%(w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30%(w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40%(w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80%(w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 75%(w/w), about 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about90% (w/w) of zoledronic acid.

Any suitable amount of zoledronic acid may be used. Some solid or liquidoral dosage forms, or units of oral dosage forms (referred tocollectively herein as “oral dosage form(s)”) may contain about 0.005 mgto about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10mg, about 0.2 mg to about 5 mg, about 1 mg to about 500 mg, about 1 mgto about 50 mg, about 10 mg to about 250 mg, about 100 mg to about 300mg, about 20 mg to about 200 mg, about 20 mg to about 150 mg, about 30mg to about 100 mg, about 1 mg to about 1,000 mg, about 10 mg to about50 mg, about 10 mg to about 300 mg, about 10 mg to about 150 mg, about10 mg to about 100 mg, about 40 mg to about 150 mg, about 10 mg to about600 mg, about 40 mg to about 600 mg, about 40 mg to about 2000 mg, about40 mg to about 800 mg, about 25 mg to about 800 mg, about 30 mg to about800 mg, about 10 mg to about 500 mg, about 50 mg to about 150 mg, about50 mg, about 100 mg, about 50 mg to about 500 mg, about 100 mg to about2000 mg, about 300 mg to about 1500 mg, about 200 mg to about 1000 mg,about 100 mg to about 500 mg, or about 150 mg of zoledronic acid, or anyamount of zoledronic in a range bounded by, or between, any of thesevalues. In some embodiments, the oral zoledronic acid is administereddaily, weekly, monthly, every two or three months, once a year, or twicea year.

In some embodiments, an oral dosage form may contain about 10 mg/m² toabout 20 mg/m², about 15 mg/m² to about 20 mg/m², about 18 mg/m², about80 mg/m² to about 150 mg/m², about 90 mg/m² to about 150 mg/m², about100 mg/m² to about 150 mg/m² of zoledronic acid, or any amount ofzoledronic in a range bounded by, or between, any of these values. Alldosage ranges or amounts expressed in mg/m² are based upon the bodysurface area of the mammal.

In some embodiments the daily oral dose of zoledronic acid is about0.005 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg toabout 10 mg, about 0.2 mg to about 5 mg, or any amount of zoledronicacid in a range bounded by, or between, any of these values. In someembodiments, the daily or dose of zoledronic acid is less than about 35mg/m², less than about 30 mg/m², less than about 25 mg/m², about 1 mg/m²to about 35 mg/m², about 1 mg/m² to about 30 mg/m², about 1.5 mg/m² toabout 25 mg/m², about 1.8 mg/m² to about 20 mg/m², about 10 mg/m² toabout 20 mg/m², about 10 mg/m² to about 30 mg/m², about 15 mg/m² toabout 20 mg/m², about 18 mg/m², or any amount of zoledronic acid in arange bounded by, or between, any of these values.

In some embodiments the weekly oral dose of zoledronic acid is about 1mg to about 1000 mg, about 1 mg to about 500 mg, about 10 mg to about250 mg, about 100 mg to about 300 mg, about 10 mg to about 100 mg, about10 mg to about 150 mg, about 10 mg to about 100 mg, about 10 mg to about300 mg, about 20 mg to about 150 mg, or about 30 mg to about 100 mg. Insome embodiments, the weekly oral dose of zoledronic acid is less thanabout 250 mg/m², less than about 200 mg/m², less than about 175 mg/m²,about 6 mg/m² to about 250 mg/m², about 10 mg/m² to about 210 mg/m²,about 10 mg/m² to about 170 mg/m², about 4 mg/m² to about 140 mg/m²,about 100 mg/m² to about 140 mg/m², about 126 mg/m², or any amount ofzoledronic acid in a range bounded by, or between, any of these values.The weekly oral dose may be given as a single dose, given once duringthe week, or may be given in 2, 3, 4, 5, 6, or 7 individual doses duringthe week.

In some embodiments, the monthly dose of zoledronic acid, or the amountof zoledronic acid that is administered over a period of a month, isabout 5000 mg or less, about 4000 mg or less, about 3000 mg or less,about 2000 mg or less, about 1000 mg or less, about 700 mg or less,about 600 mg or less, about 1 mg to about 4,000 mg, about 1 mg to about1,000 mg, about 10 mg to about 1000 mg, about 50 mg to about 1000 mg,about 10 mg to about 600 mg, about 40 mg to about 600 mg, about 50 mg toabout 600 mg, or about 100 mg to about 600 mg, about 40 mg to about 2000mg, about 40 mg to about 800 mg, about 50 mg to about 800 mg, or about100 mg to about 800 mg, about 40 mg to about 1000 mg, about 50 mg toabout 1000 mg, or about 100 mg to about 1000 mg, or any monthly dose ina range bounded by, or between, any of these values. In someembodiments, the monthly oral dose of zoledronic acid is less than about1000 mg/m², less than about 800 mg/m², less than about 600 mg/m², about10 mg/m² to about 1000 mg/m², about 50 mg/m² to about 800 mg/m², about70 mg/m² to about 700 mg/m², about 100 mg/m² to about 700 mg/m², about100 mg/m² to about 600 mg/m², about 50 mg/m² to about 200 mg/m², about300 mg/m² to about 600 mg/m², about 450 mg/m² to about 600 mg/m², about300 mg/m² to about 1000 mg/m², about 400 mg/m² to about 1000 mg/m²,about 500 mg/m² to about 1000 mg/m², about 400 mg/m² to about 700 mg/m²,about 500 mg/m² to about 600 mg/m², about 540 mg/m², or any amount ofzoledronic acid in a range bounded by, or between, any of these values.A monthly dose may be given as a single dose, or as two or moreindividual doses administered during the month. In some embodiments, themonthly dose is administered in 2 or 3 weekly doses. In someembodiments, the monthly dose is administered in 4 or 5 weekly doses. Insome embodiments, the monthly dose is administered in 28 to 31 dailydoses. In some embodiments, the monthly dose is administered in 5 to 10individual doses during the month. The monthly dose may be administeredfor only 1 month, or may be repeatedly administered for 2 or moremonths.

The oral zoledronic acid, or disodium salt thereof, may be administeredin combination with about 0.1 mg to about 10 mg of zoledronic acid, or asalt thereof, administered parenterally, such as intravenously. In someembodiments, about 50 mg, about 100 mg, or about 150 mg of the disodiumsalt of zoledronic acid is administered orally in combination with 1 mgparenteral, such as intravenous, zoledronic acid. In some embodimentsthe parenteral dose of zoledronic acid is about 0.25 mg to about 25 mg,about 0.25 mg to about 10 mg, or about 0.5 mg to about 7.5 mg.

With respect to oral administration of zoledronic acid, or anotherbisphosphonate, for the treatment of pain associated with inflammation,arthritis, CRPS, or any other condition recited herein, it may helpfulif the mammal or human being to which the zoledronic acid isadministered does not eat food or drink beverage, (other than any waterrequired to swallow the oral dosage form) for at least about 1 hour, atleast about 2 hours, at least about 4 hours, at least about 6 hours, atleast about 8 hours, at least about 10 hours, or at least about 12 hoursbefore the zoledronic acid is administered. It may also be helpful ifthe mammal or human being to which the zoledronic acid is administereddoes not eat food or drink beverage for at least about 30 minutes, atleast about 1 hour, at least about 2 hours, at least about 3 hours, orat least about 4 hours after the zoledronic acid is administered. Insome embodiments, a human being to which the zoledronic acid isadministered avoids lying down, or remains upright or sits upright, forat least about 30 minutes or about 1 hour after receiving a dosage formcontaining zoledronic acid. Avoiding food or beverage before or afteroral administration of zoledronic acid can improve the bioavailabilityof the zoledronic acid.

The oral bioavailability of zoledronic acid in a dosage form can vary.Some dosage forms may have ingredients added to enhance thebioavailability. However, bioavailability enhancement is not necessaryfor an oral dosage form to be effective. In some embodiments, the dosageform is substantially free of bioavailability-enhancing agents. In someembodiments, an oral dosage form may have an oral bioavailability ofzoledronic acid of about 0.01% to about 10%, about 0.1% to about 7%,about 0.1% to about 5%, etc. Without ingredients or other methods toenhance bioavailability, zoledronic acid typically has a lowbioavailability in an oral dosage form. In some embodiments, the oralbioavailability of zoledronic acid is unenhanced or substantiallyunenhanced. For example, the oral bioavailability of zoledronic acid canbe about 0.01% to about 5%, about 0.01% to about 4%, about 0.1% to about3%, about 0.1% to about 2%, about 0.2% to about 2%, about 0.2% to about1.5%, about 0.3% to about 1.5%, about 0.3% to about 1%, about 0.1% toabout 0.5%, about 0.3% to about 0.5%, about 0.5% to about 1%, about 0.6%to about 0.7%, about 0.7% to about 0.8%, about 0.8% to about 0.9%, about0.9%, about 1% to about 1.1%, about 1.1% to about 1.2%, about 1.2% toabout 1.3%, about 1.3% to about 1.4%, about 1.4% to about 1.5%, about1.5% to about 1.6%, about 1.6% to about 1.8%, or about 1.8% to about 2%.

One embodiment is a pharmaceutical composition comprising zoledronicacid wherein the oral bioavailability of zoledronic acid in the dosageform is from about 0.01% to about 10%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.01% to about 5%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.1% to about 7%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.1% to about 5%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.1% to about 3%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.1% to about 2%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.2% to about 2%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.2% to about 1.5%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.3% to about 1.5%.

In some embodiments, the or bioavailability of zoledronic acid in thedosage form is about 0.3% to about 1.0%.

In some embodiments, an oral dosage form comprises about 10 mg to about300 mg of zoledronic acid, and is administered daily for about 2 toabout 15 consecutive days. This regimen may be repeated once monthly,once every two months, once every three months, once every four months,once every five months, once every six months, once yearly, or onceevery two years.

In some embodiments, an oral dosage form comprises about 10 mg to about150 mg or about 10 mg to about 100 mg of zoledronic acid, and isadministered daily for about 2 to about 15 consecutive days. Thisregimen may be repeated once monthly, once every two months, once everythree months, once every four months, once every five months, once everysix months, once yearly, or once every two years.

In some embodiments, an oral dosage form comprises about 10 mg to about150 mg or about 10 mg to about 100 mg of zoledronic acid, and isadministered daily for about 5 to about 10 consecutive days. Thisregimen may be repeated once monthly, once every two months, once everythree months, once every four months, once every five months, once everysix months, once yearly, or once every two years.

In some embodiments, an oral dosage form comprises about 40 mg to about150 mg of zoledronic acid, and is administered daily for about 5 toabout 10 consecutive days. This regimen may be repeated once monthly,once every two months, once every three months, once every four months,once every five months, once every six months, once yearly, or onceevery two years.

In some embodiments, the oral zoledronic acid may be administered as onedose of about 100 mg to about 2000 mg. In some embodiments, the oralzoledronic acid may be administered as one dose of about 300 mg to about1500 mg. In some embodiments, the oral zoledronic acid may beadministered as one dose of about 200 mg to about 1000 mg. The dose ofzoledronic acid may be administered in a single or divided dose.

Zoledronic acid may be formulated for oral administration, for example,with an inert diluent or with an edible carrier, or it may be enclosedin hard or soft shell gelatin capsules, compressed into tablets, orincorporated directly with the food of the diet. For oral therapeuticadministration, the active compound may be incorporated with anexcipient and used in the form of ingestible tablets, buccal tablets,coated tablets, troches, capsules, elixirs, dispersions, suspensions,solutions, syrups, wafers, patches, and the like.

Tablets, troches, pills, capsules and the like may also contain one ormore of the following: a binder such as gum tragacanth, acacia, cornstarch or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; a sweetening agentsuch as sucrose, lactose or saccharin; or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the unit dosageform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier. Various other materials may be present ascoating, for instance, tablets, pills, or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Itmay be desirable for material in a dosage form or pharmaceuticalcomposition to be pharmaceutically pure and substantially non toxic inthe amounts employed.

Some compositions or dosage forms may be a liquid, or may comprise asolid phase dispersed in a liquid.

Zoledronic acid may be formulated for parental or intraperitonealadministration. Solutions of the active compounds as free acids orpharmacologically acceptable salts can be prepared in water suitablymixed with a surfactant, such as hydroxypropylcellulose. A dispersioncan also have an oil dispersed within, or dispersed in, glycerol, liquidpolyethylene glycols, and mixtures thereof. Under ordinary conditions ofstorage and use, these preparations may contain a preservative toprevent the growth of microorganisms.

In some embodiments, an oral dosage form may comprise a silicifiedmicrocrystalline cellulose such as Prosolv. For example, about 20%(wt/wt) to about 70% (wt/wt), about 10% (wt/wt) to about 20% (wt/wt),about 20% (wt/wt) to about 40% (wt/wt), about 25% (wt/wt) to about 30%(wt/wt), about 40% (wt/wt) to about 50% (wt/wt), or about 45% (wt/wt) toabout 50% (wt/wt) silicified microcrystalline cellulose may be presentin an oral dosage form or a unit of an oral dosage form.

In some embodiments, an oral dosage form may comprise a crosslinkedpolyvinylpyrrolidone such as crospovidone. For example, about 1% (wt/wt)to about 10% (wt/wt), about 1% (wt/wt) to about 5% (wt/wt), or about 1%(wt/wt) to about 3% (wt/wt) crosslinked polyvinylpyrrolidone may bepresent in an oral dosage form or a unit of an oral dosage form.

In some embodiments, an oral dosage form may comprise a fumed silicasuch as Aerosil. For example, about 0.1% (wt/wt) to about 10% (wt/wt),about 0.1% (wt/wt) to about 1% (wt/wt), or about 0.4% (wt/wt) to about0.6% (wt/wt) fumed silica may be present in an oral dosage form or aunit of an oral dosage form.

In some embodiments, an oral dosage form may comprise magnesiumstearate. For example, about 0.1% (wt/wt) to about 10% (wt/wt), about0.1% (wt/wt) to about 1% (wt/wt), or about 0.4% (wt/wt) to about 0.6%(wt/wt) magnesium stearate may be present in an oral dosage form or aunit of an oral dosage form.

An oral dosage form comprising zoledronic acid or another bisphosphonatemay be included in a pharmaceutical product comprising more than oneunit of the oral dosage form.

A pharmaceutical product containing or dosage forms for daily use cancontain 28, 29, 30, or 31 units of the oral dosage form for a monthlysupply. An approximately 6 week daily supply can contain 40 to 45 unitsof the oral dosage form. An approximately 3 month daily supply cancontain 85 to 95 units of the oral dosage form. An approximatelysix-month daily supply can contain 170 to 200 units of the oral dosageform. An approximately one year daily supply can contain 350 to 380units of the oral dosage form.

A pharmaceutical product containing or dosage forms for weekly use cancontain 4 or 5 units of the oral dosage form for a monthly supply. Anapproximately 2 month weekly supply can contain 8 or 9 units of the oraldosage form. An approximately 6 week weekly supply can contain about 6units of the oral dosage form. An approximately 3 month weekly supplycan contain 12, 13 or 14 units of the oral dosage form. An approximatelysix-month weekly supply can contain 22 to 30 units of the oral dosageform. An approximately one year weekly supply can contain 45 to 60 unitsof the oral dosage form.

A pharmaceutical product may accommodate other dosing regimes. Forexample, a pharmaceutical product may comprise 5 to 10 units of the oraldosage form, wherein each unit of the oral dosage form contains about 40mg to about 150 mg of zoledronic acid. Some pharmaceutical products maycomprise 1 to 10 units of the oral dosage form, wherein the productcontains about 200 mg to about 2000 mg of zoledronic acid. For such aproduct, each unit of the oral dosage form may be taken daily for 1 to10 days or 5 to 10 days during a month, such as at the beginning of amonth.

Some oral dosage forms comprising zoledronic acid or a salt thereof mayhave enteric coatings or film coatings.

In the examples below, zoledronic acid was administered in the disodiumsalt form as disodium zoledronate tetrahydrate. No bioavailabilityenhancing agents were used in the test compositions.

Example 1 Effect of Orally Administered Zoledronic Acid in Rat Model ofInflammatory Pain

Method:

The effect of orally administered zoledronic acid on inflammatory painwas examined using the rat complete Freund's adjuvant (CFA) model.Inflammatory pain was induced by injection of 100% CFA in a 75 μL volumeinto the left hind paws of Sprague-Dawley rats on day 0, followed byassessments on days 1-3. Animals were orally administered vehicle(control), zoledronic acid 18 mg/m² (or 3 mg/kg), zoledronic acid 120mg/m² (or 20 mg/kg), or zoledronic acid 900 mg/m² (or 150 mg/kg) dailyon days 1-3. Drug was dissolved in distilled water and prepared freshdaily. Animals were fasted prior to dosing. Under current FDA guidelinesfor extrapolating starting dosages from animals to humans, dosagesexpressed in mg/m² are considered equivalent between mammalian species.Thus, for example, 18 mg/m² in a rat is considered equivalent to 18mg/m² in a human being, while 3 mg/kg in a rat may not be equivalent to3 mg/kg in a human being.

Values for inflammatory pain (mechanical hyperalgesia) in the vehicleand drug-treated animals were obtained on day 0 prior to CFA injection,and at baseline and post-treatment on days 1-3. Pain was assessed usinga digital Randall-Selitto device (dRS; IITC Life Sciences, WoodlandHills, Calif.). Animals were placed in a restraint sling that suspendedthe animal, leaving the hind limbs available for testing. Pawcompression threshold was measured by applying increasing pressure tothe plantar surface of the hind paw with a dome-shaped tip placedbetween the 3rd and 4th metatarsus. Pressure was applied gradually overapproximately 10 seconds. Measurements were taken from the firstobserved nocifensive behavior of vocalization, struggle or withdrawal. Acut-off value of 300 g was used to prevent injury to the animal.

Reversal of inflammatory pain was calculated according to the formula:% reversal=(Post-treatment−Post-CFA baseline)/(Pre-CFA baseline−Post-CFAbaseline)×100.

The experiment was carried out using 9-10 animals per group.

Results:

Oral administration of zoledronic acid significantly improvedinflammatory pain thresholds compared to vehicle. Pain thresholdmeasurements taken at various times are shown in FIG. 1. Paw compressionthresholds in the 18 mg/m² group were higher than for vehicle during theentire measurement period after 30 minutes from the start of treatment.On day three, paw compression thresholds for both the 18 mg/m² and 900mg/m² groups were greater than for vehicle. An improvement in painthreshold of 49% and 83% from baseline was observed for the 18 mg/m² andthe 900 mg/m² groups respectively.

Orally administered zoledronic acid produced a 29% reversal ofinflammatory pain at the 18 mg/m², and a 48% reversal at the 900 mg/m²dose. This magnitude of effect is comparable to that obtained withclinical doses of commercially available NSAIDs when tested in a similarmodel of inflammatory pain. Under current FDA guidelines, the referencebody surface area of a human adult is 1.62 m². Thus, a daily dose of 18mg/m² corresponds to a monthly dose of about 500-560 mg/m² or a humandose of about 800-900 mg.

Surprisingly, the two higher doses resulted in thresholds that werelower than vehicle on the first two days of dosing. The 120 mg/m² groupwas approximately equal or inferior to vehicle at all time points duringthe assessment period. While the 900 mg/m² group showed effectiveness onday 3, this result was accompanied by significant toxicity necessitatingeuthanization of all the animals in this group two days after cessationof dosing.

Example 2 Effect of Orally Administered Zoledronic Acid in Rat Model ofArthritis Pain

Method

The effect of orally administered zoledronic acid on arthritis pain wasexamined in the rat complete Freund's adjuvant (CFA) model of arthritispain. In this model, injection of 100% complete Freund's adjuvant (CFA)in a 75 μL volume into the left hind paws is followed by a 10-14 dayperiod to allow for the development of arthritis pain. Animals wereorally administered vehicle (control), zoledronic acid 54 mg/m² (or 9mg/kg), or zoledronic acid 360 mg/m² (or 60 mg/kg), divided in threeequal daily doses on the first three days post CFA injection. Drug wasdissolved in distilled water and prepared fresh daily. Animals werefasted prior to dosing.

Arthritis pain (mechanical hyperalgesia) in the vehicle and drug-treatedanimals was evaluated on day 14 post CFA injection using a digitalRandall-Selitto device (dRS; IITC Life Sciences, Woodland Hills,Calif.). Animals were placed in a restraint sling that suspended theanimal, leaving the hind limbs available for testing. Paw compressionthreshold was measured by applying increasing pressure to the plantarsurface of the hind paw with a dome-shaped tip placed between the 3rdand 4th metatarsus. Pressure was applied gradually over approximately 10seconds. Measurements were taken from the first observed nocifensivebehavior of vocalization, struggle or withdrawal. A cut-off value of 300g was used to prevent injury to the animal.

Reversal of arthritis pain in the ipsilateral (CFA-injected) paw wascalculated according to the formula:% reversal=(ipsilateral drug threshold−ipsilateral vehiclethreshold)/(contralateral vehicle threshold−ipsilateral vehiclethreshold)×100.

The experiment was carried out using 7-10 animals per group.

Results:

Oral administration of zoledronic acid significantly improved arthritispain thresholds compared to vehicle. As shown in FIGS. 2A and 2B, orallyadministered zoledronic acid produced a dose-dependent reversal ofarthritis pain. A reversal of 33% was observed in the 54 mg/m² group,and reversal of 54% was observed in the 360 mg/m² group. Under currentFDA guidelines, the reference body surface area of a human adult is 1.62m². Thus, 54 mg/m² in a rat is equivalent to an implied human dose ofabout 87 mg, and 360 mg/m² in a rat is equivalent to an implied humandose of about 583 mg.

Example 3 Treatment of Complex Regional Pain Syndrome with OrallyAdministered Zoledronic Acid

The effect of orally administered zoledronic acid was examined in therat tibia fracture model of complex regional pain syndrome (CRPS). CRPSwas induced in the rats by fracturing the right distal tibias of theanimals and casting the fractured hindpaws for 4 weeks, as described inGuo T Z et al. (Pain. 2004; 108:95-107). This animal model has beenshown to replicate the inciting trauma, natural history, signs,symptoms, and pathologic changes observed in human CRPS patients(Kingery W S et al., Pain. 2003; 104:75-84).

Animals were orally administered either vehicle (control) or zoledronicacid, in a dosage of 18 mg/m²/day (3 mg/kg/day) for 28 days, starting onthe day of fracture and casting. Drug was dissolved in distilled waterand administered by gavage. Animals were fasted for 4 hours before and 2hours after dosing. At the end of the 28-day period, casts were removed,and on the following day, the rats were tested for hindpaw pain, edema,and warmth.

Pain Assessments

Pain was assessed by measuring hyperalgesia, and weight bearing.

To measure hyperalgesia, an up-down von Frey testing paradigm was used.Rats were placed in a clear plastic cylinder (20 cm in diameter) with awire mesh bottom and allowed to acclimate for 15 minutes. The paw wastested with one of a series of eight von Frey hairs ranging in stiffnessfrom 0.41 g to 15.14 g. The von Frey hair was applied against thehindpaw plantar skin at approximately midsole, taking care to avoid thetori pads. The fiber was pushed until it slightly bowed and then it wasjiggled in that position for 6 seconds. Stimuli were presented at aninterval of several seconds. Hindpaw withdrawal from the fiber wasconsidered a positive response. The initial fiber presentation was 2.1 gand the fibers were presented according to the up-down method of Dixonto generate six responses in the immediate vicinity of the 50%threshold. Stimuli were presented at an interval of several seconds.

An incapacitance device (IITC Inc. Life Science, Woodland, Calif., USA)was used to measure hindpaw weight bearing, a postural effect of pain.The rats were manually held in a vertical position over the apparatuswith the hindpaws resting on separate metal scale plates and the entireweight of the rat was supported on the hindpaws. The duration of eachmeasurement was 6 seconds and 10 consecutive measurements were taken at60-second intervals. Eight readings (excluding the highest and lowestones) were averaged to calculate the bilateral hindpaw weight-bearingvalues. Weight bearing data were analyzed as the ratio between right(fracture) and left hindpaw weight bearing values ((2R/(R+L))×100%).

Edema Assessment

A laser sensor technique was used to determine the dorsal-ventralthickness of the hindpaw. Before baseline testing the bilateral hindpawswere tattooed with a 2 to 3 mm spot on the dorsal skin over the midpointof the third metatarsal. For laser measurements each rat was brieflyanesthetized with isoflurane and then held vertically so the hindpawrested on a table top below the laser. The paw was gently held flat onthe table with a small metal rod applied to the top of the ankle joint.Using optical triangulation, a laser with a distance measuring sensorwas used to determine the distance to the table top and to the top ofthe hindpaw at the tattoo site and the difference was used to calculatethe dorsal-ventral paw thickness. The measurement sensor device used inthese experiments (4381 Precicura, Limab, Goteborg, Sweden) has ameasurement range of 200 mm with a 0.01 mm resolution.

Hindpaw Temperature Measurement

The temperature of the hindpaw was measured using a fine wirethermocouple (Omega, Stanford, Conn., USA) applied to the paw skin. Sixsites were tested per hindpaw. The six measurements for each hindpawwere averaged for the mean temperature.

Results

As illustrated in FIG. 3, treatment with orally administered zoledronicacid reversed pain, restored weight bearing, and prevented edema ascompared to vehicle treated animals.

As illustrated in FIG. 4, von Frey pain thresholds for the right(fracture) hindpaw were reduced by 72% versus the contralateral (normal)hindpaw in vehicle treated animals. Zoledronate treatment reversedfracture induced pain by 77% as compared to vehicle treatment.

As illustrated in FIG. 5, reduction in weight bearing, a postural effectof pain, was significantly higher in the vehicle treated group ascompared to the zoledronic acid treated group. Weight bearing on thefracture hindlimb was reduced to 55% of normal in the vehicle treatedgroup. Zoledronate treatment significantly restored hindlimb weightbearing as compared to vehicle treatment (86% of normal).

As illustrated in FIG. 6, the expected increase in hindpaw thickness wasgreater in the vehicle treated group as compared to the zoledronic acidtreated group, reflecting the development of edema. Zoledronatetreatment reduced hindpaw edema by 60% versus vehicle treatment.

Zoledronic acid reduced hindpaw warmth by 5% versus vehicle treatment.

The daily dose in the above experiment was 18 mg/m²/day. Under currentFDA guidelines, the reference body surface area of a human adult is 1.62m². Thus, a daily dose of 18 mg/m² corresponds to a monthly dose ofabout 500-560 mg/m² or a human dose of about 800-900 mg.

Example 6 Solubility of Disodium Salt of Zoledronic Acid

The aqueous solubility of zoledronic acid and disodium zoledronatetetrahydrate was determined. One gram of the test compound was measuredin to a beaker. Demineralized water (pH 5.5) was then added in smallincrements to the test compound, and sonification was applied to themixture. The procedure was continued until complete dissolution wasachieved. Full dissolution was determined to have been reached when aclear solution was present with no visible material. The volume of waterrequired to reach full dissolution was used to calculate a solubilityvalue expressed in grams per 100 mL. The procedure was performed foreach compound.

Results

As shown in FIG. 7, the aqueous solubility of disodium zoledronatetetrahydrate is approximately 50 times that of zoledronic acid. Disodiumzoledronate tetrahydrate has a solubility of 12.5 g/100 mL compared toonly 0.25 g/100 mL for zoledronic acid.

Example 7 Bioavailability of Orally Administered Zoledronic Acid andDisodium Zoledronate

Tablets were manufactured containing either pure zoledronic acid or thedisodium salt of zoledronic acid (disodium zoledronate tetrahydrate).Both types of tablets contained 50 mg of zoledronic acid equivalent pertablet. Identical excipients were used in both types of tablets, withamounts adjusted to account for the difference in molecular weightsbetween the acid and the disodium salt.

Beagle dogs were orally administered tablets containing 150 mgzoledronic acid equivalent either in the form of disodium zoledronate(Group 1) or pure zoledronic acid (Group 2). Each animal was given three50 mg equivalent tablets (150 mg total), which were administeredtogether. The animal's oral cavity was wetted with water before placingthe tablets on the back of the animal's tongue. Animals were fastedbefore and after dosing. Animals were 6 to 9 months of age and weighed 6to 10 kg on the day of dosing. There were three dogs per group.

Serial blood samples were collected from each animal by venipuncture ofthe jugular vein at various points after dosing for measurement ofplasma concentrations of zoledronic acid. Blood samples were collectedinto chilled tubes containing K₂EDTA as the anticoagulant. Samples werethen centrifuged at approximately 3000 rpm at +4° C. for 10 minutes forplasma derivation. Plasma concentrations of zoledronic acid weremeasured using an LC/MS/MS method.

Results

The average plasma concentrations of zoledronic acid for each group ofdogs is summarized in Table 1 and illustrated in FIG. 8. Detectableplasma levels of zoledronic acid were observed for the entire 48 hoursthat they were measured.

TABLE 1 Zoledronic Acid plasma concentrations in beagle dogs Plasma Timeconcentration (hour) (ng/mL) Group 1 Disodium Zoledronate 0 0.00 (N = 3)Tablets 0.25 1193.97 (150 mg acid equivalent) 0.5 1852.12 0.75 1776.51 11626.56 2 640.57 4 136.93 6 53.11 8 26.97 12 13.74 24 6.78 48 5.39 Group2 Zoledronic Acid Tablets 0 0.00 (N = 3) (150 mg acid equivalent) 0.25390.92 0.5 846.19 0.75 819.15 1 831.77 2 477.76 4 90.11 6 28.22 8 15.1012 6.13 24 3.18 48 1.84

Disodium zoledronate produced significantly higher plasma levelszoledronic acid than pure zoledronic acid, indicating improved oralabsorption with the salt form. Measured using peak plasma concentrations(C_(max)), the disodium salt resulted in a 119% actual and 74%weight-adjusted increase in bioavailability as compared to purezoledronic acid. Measured using area under the plasma concentrationcurve (AUC_(0-∞)), bioavailability was 84% and 46% greater with thedisodium salt than with pure zoledronic acid, on an actual andweight-adjusted basis respectively. The average AUC_(0-∞) for thedisodium salt was 4073 ng·hr/mL and the average AUC_(0-∞) for the diacidwas 2217 ng·hr/mL. The AUC_(0-∞) was found to be dose proportional.Thus, for beagle dogs similar to those tested, about 3 mg to about 4 mgof the disodium salt would be expected to result in an AUC_(0-∞) ofabout 100 ng·hr/mL, and about 7 mg to about 8 mg of the disodium saltwould be expected to result in an AUC_(0-∞) of about 200 ng·hr/mL.

Example 8

Tablets were prepared by blending zoledronic acid, either in the form ofthe free acid or the disodium salt, with identical excipients. Fordosage forms with a greater amount of active, the amount of theexcipients was reduced proportionally to keep the weight of the tabletat about 100 mg. After blending, the ingredients were compressed atvarying pressures, followed by a film coating. The resulting tabletswere then tested for hardness using a Dr. Schleuniger Pharmatron 8MTablet Hardness Tester. The results are shown in Table 2 and FIG. 9.

TABLE 2 Hardness (kPa) Compression Disodium Disodium Force Diacid SaltSalt (psi) 50 mg 50 mg 71 mg 800 4.0 8.7 4.8 1100 6.1 11.2 6.8 1500 7.713.7 7.4 2000 8.7 16.3 10.7 2400 8.7 11.3 3000 11.4 14.1 4400 12.5 14.95500 12.8 18.2 6100 13.0

The following embodiments are specifically contemplated:

Embodiment 1 A method of relieving inflammatory pain comprisingadministering an oral dosage form containing zoledronic acid to a mammalin need thereof, wherein the mammal receives a total monthly dose ofzoledronic acid that is about 800 mg/m² or less based upon the bodysurface area of the mammal.

Embodiment 2 The method of embodiment 1, wherein the mammal is a humanbeing that receives a total monthly dose of zoledronic acid that isabout 30 mg/m² to about 700 mg/m².

Embodiment 3 The method of embodiment 2, wherein the total monthly doseis administered in 4 or 5 weekly doses.

Embodiment 4 The method of embodiment 2, wherein the total monthly doseis administered in 28 to 31 daily doses.

Embodiment 5 The method of embodiment 2, wherein the total monthly doseis administered in 5 to 10 individual doses during the month.

Embodiment 6 The method of embodiment 1, wherein the mammal is a humanbeing that receives a total weekly dose of zoledronic acid that is about10 mg to about 300 mg.

Embodiment 7 The method of embodiment 6, wherein the total weekly doseis a single dose, administered once a week.

Embodiment 8 The method of embodiment 6, wherein the total weekly doseis administered in 2 to 7 individual doses during the week.

Embodiment 9 The method of embodiment 1, wherein the mammal is a humanbeing that receives a total weekly dose of zoledronic acid that is about10 mg to about 150 mg.

Embodiment 10 The method of any preceding embodiment, wherein the mammalexperiences significant pain relief more than 3 hours afteradministration of the dosage form.

Embodiment 11 The method of embodiment 10, wherein the mammalexperiences significant pain relief during at least a part of a timefrom about 3 hours to about 24 hours after administration of the dosageform.

Embodiment 12 The method of embodiment 10, wherein the mammalexperiences significant pain relief during at least a part of a timefrom about 3 hours to about 3 weeks after administration of the dosageform.

Embodiment 13 A method of relieving inflammatory pain comprisingadministering an oral dosage form containing zoledronic acid to a mammalin need thereof, wherein the oral dosage form contains about 10 mg/m² toabout 20 mg/m² of zoledronic acid based upon the body surface area ofthe mammal.

Embodiment 14 The method of embodiment 13, wherein the oral dosage formcontains about 15 mg/m² to about 20 mg/m² of zoledronic acid based uponthe body surface area of the mammal.

Embodiment 15 A method of relieving inflammatory pain comprising orallyadministering to a mammal in need thereof, about 300 mg/m² to about 600mg/m² of zoledronic acid per month to the mammal, based upon the bodysurface area of the mammal.

Embodiment 16 The method of embodiment 15, comprising orallyadministering about 450 mg/m² to about 600 mg/m² of zoledronic acid permonth to the mammal, based upon the body surface area of the mammal.

Embodiment 17 The method of any preceding embodiment, wherein the mammalis not suffering from bone metastasis.

Embodiment 18 The method of any preceding embodiment, wherein the mammalis not suffering from cancer.

Embodiment 19 The method of any preceding embodiment, wherein thezoledronic acid is administered as a salt of a dianion of zoledronicacid.

Embodiment 20 A method of relieving pain associated with an arthritiscomprising administering an oral dosage form containing zoledronic acidto a human being in need thereof.

Embodiment 21 The method of embodiment 20, wherein the human beingreceives a total monthly dose of zoledronic acid that is about 40 mg toabout 2000 mg.

Embodiment 22 The method of embodiment 21, wherein the total monthlydose is administered in 4 or 5 weekly doses.

Embodiment 23 The method of embodiment 21, wherein the total monthlydose is administered in 28 to 31 daily doses.

Embodiment 24 The method of embodiment 21, wherein the total monthlydose is administered in 5 to 10 individual doses during the month.

Embodiment 25 The method of embodiment 20, wherein the human beingreceives a total weekly dose of zoledronic acid that is about 100 mg toabout 300 mg.

Embodiment 26 The method of embodiment 25, wherein the total weekly doseis a single dose, administered once a week.

Embodiment 27 The method of embodiment 25, wherein the total weekly doseis administered in 2 to 7 individual doses during the week.

Embodiment 28 The method of embodiment 20, wherein the human beingreceives a total weekly dose of zoledronic acid that is about 10 mg toabout 100 mg.

Embodiment 29 The method of any of embodiments 20-28, wherein the humanbeing experiences significant pain relief more than 3 hours afteradministration of the dosage form.

Embodiment 30 The method of embodiment 29, wherein the human beingexperiences significant pain relief during at least a part of a timefrom about 3 hours to about 24 hours after administration of the dosageform.

Embodiment 31 The method of embodiment 29, wherein the human beingexperiences significant pain relief during at least a part of a timefrom about 3 hours to about 3 weeks after administration of the dosageform.

Embodiment 32 The method of any of embodiments 20-31, wherein the dosageform contains about 10 mg/m² to about 20 mg/m² of zoledronic acid basedupon the body surface area of the human being.

Embodiment 33 The method of embodiment 32, wherein the dosage formcontains about 15 mg/m² to about 20 mg/m² of zoledronic acid based uponthe body surface area of the human being.

Embodiment 34 rein about 50 mg/m² to about 200 mg/m² of zoledronic acidis orally administered per month, based upon the body surface area ofthe human being.

Embodiment 35 The method of any of embodiments 20-31, wherein the dosageform contains about 80 mg/m² to about 150 mg/m² of zoledronic acid basedupon the body surface area of the human being.

Embodiment 36 The method of embodiment 35, wherein about 300 mg/m² toabout 1000 mg/m² of zoledronic acid is orally administered per month,based upon the body surface area of the human being.

Embodiment 37 The method of any of embodiments 20-36, wherein the humanbeing is not suffering from bone metastasis.

Embodiment 38 The method of any of embodiments 20-37, wherein the humanbeing is not suffering from cancer.

Embodiment 39 The method of any preceding embodiment, wherein thezoledronic acid is in the disodium salt form.

Embodiment 40 An or dosage form comprising zoledronic acid, wherein theoral bioavailability of zoledronic acid in the dosage form is about0.01% to about 4%.

Embodiment 41 The oral dosage form of embodiment 40, wherein the oraldosage form contains about 10 mg to about 300 mg of zoledronic acid.

Embodiment 42 The oral dosage form of embodiment 40, wherein the oraldosage form contains about 10 mg to about 50 mg of zoledronic acid.

Embodiment 43 The oral dosage form of any of embodiments 40-42, whereinthe oral bioavailability of zoledronic acid in the dosage form is about0.1% to about 2%.

Embodiment 44 A pharmaceutical product comprising more than one unit ofan oral dosage form of embodiment 40.

Embodiment 45 The pharmaceutical product of embodiment 44, wherein eachunit of the oral dosage form contains about 1 mg to about 50 mg ofzoledronic acid.

Embodiment 46 The pharmaceutical product of embodiment 45, comprising28, 29, 30, or 31 units of the oral dosage form, for a total of about 28mg to about 1600 mg of zoledronic acid to be administered in about 1month.

Embodiment 47 The pharmaceutical product of embodiment 45, comprising 85to 95 units of the oral dosage form, for a total of about 85 mg to about4800 mg of zoledronic acid to be administered in about 3 months.

Embodiment 48 The pharmaceutical product of embodiment 45, comprising170 to 200 units of the oral dosage form, for a total of about 170 mg toabout 10,000 mg of zoledronic acid to be administered in about 6 months.

Embodiment 49 The pharmaceutical product of embodiment 45, comprising350 to 380 units of the oral dosage form, for a total of about 350 mg toabout 19,000 mg of zoledronic acid to be administered in about 1 year.

Embodiment 50 The pharmaceutical product of embodiment 44, wherein eachunit of the oral dosage form contains about 10 mg to about 300 mg.

Embodiment 51 The pharmaceutical product of embodiment 50, comprising 4or 5 units of the oral dosage form, for a total of about 40 mg to about1500 mg of zoledronic acid to be administered within a period of about 1month.

Embodiment 52 The pharmaceutical product of embodiment 50, comprising 8or 9 units of the oral dosage form, for a total of about 80 mg to about2700 mg of zoledronic acid to be administered in about 2 months.

Embodiment 53 The pharmaceutical product of embodiment 50, comprising12, 13 or 14 units of the oral dosage form, for a total of about 120 mgto about 4200 mg of zoledronic acid to be administered in about 3months.

Embodiment 54 The pharmaceutical product of embodiment 50, comprising 22to 30 units of the oral dosage form, for a total of about 220 mg toabout 9000 mg of zoledronic acid to be administered in about 6 months.

Embodiment 55 The pharmaceutical product of embodiment 50, comprising 45to 60 units of the oral dosage form, for a total of about 450 mg toabout 18000 mg of zoledronic acid to be administered in about 1 year.

Embodiment 56 The pharmaceutical product of embodiment 44, comprising 1to 10 units of the oral dosage form, wherein the product contains about200 mg to about 2000 mg of zoledronic acid.

Embodiment 57 The oral dosage form of any preceding embodiment, whereinthe zoledronic acid is in the form of a sodium salt.

Embodiment 58 The oral dosage form of any preceding embodiment, whereinthe zoledronic acid is in a form that has an aqueous solubility greaterthan 1% (w/v).

Embodiment 59 The oral dosage form of any preceding embodiment, whereinthe zoledronic acid is in a form that has an aqueous solubility of about5% (w/v) to about 50% (w/v).

Embodiment 60 An oral dosage form comprising zoledronic acid and anexcipient, wherein the zoledronic acid is in a form that has an aqueoussolubility greater than 1% (w/v).

Embodiment 61 The oral dosage form of embodiment 60, wherein thezoledronic acid is in a form that has an aqueous solubility of about 5%(w/v) to about 50% (w/v).

Embodiment 62 A method of treating complex regional pain syndromecomprising administering an oral dosage form containing zoledronic acidto a mammal in need thereof.

Embodiment 63 The method of embodiment 62, wherein the mammal is a humanbeing that receives an amount of zoledronic acid that is about 30 mg/m²to about 700 mg/m² in a period of one month or less.

Embodiment 64 The method of embodiment 63, wherein 4 or 5 weekly dosesare administered in a period of one month or less.

Embodiment 65 The method of embodiment 63, wherein 28 to 31 daily dosesare administered in a period of one month or less.

Embodiment 66 The method of embodiment 63, wherein 5 to 10 individualdoses are administered during a period of one month or less.

Embodiment 67 The method of embodiment 63, wherein about 30 mg/m² toabout 700 mg/m² of zoledronic acid is administered during only onemonth.

Embodiment 68 The method of embodiment 63, wherein about 30 mg/m² toabout 700 mg/m² of zoledronic acid is administered in a period of onemonth or less for 2 or more consecutive months.

Embodiment 69 The method of embodiment 62, wherein the mammal receivesabout 10 mg/m² to about 30 mg/m² of zoledronic acid daily.

Embodiment 70 The method of embodiment 62, wherein the mammal is a humanbeing that receives a total weekly dose of zoledronic acid that is about10 mg to about 300 mg.

Embodiment 71 The method of embodiment 70, wherein the total weekly doseis a single dose, administered once a week.

Embodiment 72 The method of embodiment 70, wherein the total weekly doseis administered in 2 to 7 individual doses during the week.

Embodiment 73 The method of any of embodiments 62-72, wherein thecomplex regional pain syndrome is complex regional pain syndrome type I.

Embodiment 74 The method of any of embodiments 62-72, wherein thecomplex regional pain syndrome is complex regional pain syndrome typeII.

Embodiment 75 The method of any preceding embodiment, wherein thezoledronic acid is in a salt form.

Embodiment 76 The method of any of embodiments 62-75, wherein the dosageform contains about 10 mg/m² to about 20 mg/m² of zoledronic acid basedupon the body surface area of the mammal.

Embodiment 77 The method of embodiment 76, wherein the dosage formcontains about 15 mg/m² to about 20 mg/m² of zoledronic acid based uponthe body surface area of the mammal.

Embodiment 78 A method of treating complex regional pain syndrome,comprising administering pamidronic acid to a human being in needthereof.

Embodiment 79 A method of treating complex regional pain syndrome,comprising administering neridronic acid to a human being in needthereof.

Embodiment 80 A method of treating complex regional pain syndrome,comprising administering olpadronic acid to a human being in needthereof.

Embodiment 81 A method of treating complex regional pain syndrome,comprising administering alendronic acid to a human being in needthereof.

Embodiment 82 A method of treating complex regional pain syndrome,comprising administering incadronic acid to a human being in needthereof.

Embodiment 83 A method of treating complex regional pain syndrome,comprising administering ibandronic acid to a human being in needthereof.

Embodiment 84 A method of treating complex regional pain syndrome,comprising administering risedronic acid to a human being in needthereof.

Embodiment 85 A method of treating pain, comprising administeringpamidronic acid to a human being in need thereof.

Embodiment 86 A method of treating pain, comprising administeringneridronic acid to a human being in need thereof.

Embodiment 87 A method of treating pain, comprising administeringolpadronic acid to a human being in need thereof.

Embodiment 88 A method of treating pain, comprising administeringalendronic acid to a human being in need thereof.

Embodiment 89 A method of treating pain, comprising administeringincadronic acid to a human being in need thereof.

Embodiment 90 A method of treating pain, comprising administeringibandronic acid to a human being in need thereof.

Embodiment 91 A method of treating pain, comprising administeringrisedronic acid to a human being in need thereof.

Embodiment 92 A method of treating arthritis pain, comprisingadministering pamidronic acid to a human being in need thereof.

Embodiment 93 A method of treating arthritis pain, comprisingadministering neridronic acid to a human being in need thereof.

Embodiment 94 A method of treating arthritis pain, comprisingadministering olpadronic acid to a human being in need thereof.

Embodiment 95 A method of treating arthritis pain, comprisingadministering alendronic acid to a human being in need thereof.

Embodiment 96 A method of treating arthritis pain, comprisingadministering incadronic acid to a human being in need thereof.

Embodiment 97 A method of treating arthritis pain, comprisingadministering ibandronic acid to a human being in need thereof.

Embodiment 98 A method of treating arthritis pain, comprisingadministering risedronic acid to a human being in need thereof.

Embodiment 99 A method of treating inflammatory pain, comprisingadministering pamidronic acid to a human being in need thereof.

Embodiment 100 A method of treating inflammatory pain, comprisingadministering neridronic acid to a human being in need thereof.

Embodiment 101 A method of treating inflammatory pain, comprisingadministering olpadronic acid to a human being in need thereof.

Embodiment 102 A method of treating inflammatory pain, comprisingadministering alendronic acid to a human being in need thereof.

Embodiment 103 A method of treating inflammatory pain, comprisingadministering incadronic acid to a human being in need thereof.

Embodiment 104 A method of treating inflammatory pain, comprisingadministering ibandronic acid to a human being in need thereof.

Embodiment 105 A method of treating inflammatory pain, comprisingadministering risedronic acid to a human being in need thereof.

Embodiment 106 A method of treating complex regional pain syndrome,comprising administering etidronic acid to a human being in needthereof.

Embodiment 107 A method of treating pain, comprising administeringetidronic acid to a human being in need thereof.

Embodiment 108 A method of treating arthritis pain, comprisingadministering etidronic acid to a human being in need thereof.

Embodiment 109 A method of treating inflammatory pain, comprisingadministering etidronic acid to a human being in need thereof.

Embodiment 110 A method of treating complex regional pain syndrome,comprising administering clodronic acid to a human being in needthereof.

Embodiment 111 A method of treating pain, comprising administeringclodronic acid to a human being in need thereof.

Embodiment 112 A method of treating arthritis pain, comprisingadministering clodronic acid to a human being in need thereof.

Embodiment 113 A method of treating inflammatory pain, comprisingadministering clodronic acid to a human being in need thereof.

Embodiment 114 A method of treating complex regional pain syndrome,comprising administering tiludronic acid to a human being in needthereof.

Embodiment 115 A method of treating pain, comprising administeringtiludronic acid to a human being in need thereof.

Embodiment 116 A method of treating arthritis pain, comprisingadministering tiludronic acid to a human being in need thereof.

Embodiment 117 A method of treating inflammatory pain, comprisingadministering tiludronic acid to a human being in need thereof.

Embodiment 118 The method of any of embodiments 78-117, wherein theactive compound is orally administered.

Embodiment 119 The method of any of embodiments 78-117, wherein theactive compound is parenterally administered.

Embodiment 120 A method of enhancing the oral bioavailability ofzoledronic acid comprising orally administering a dosage form containingzoledronic acid in the disodium salt form.

Embodiment 121 The method of embodiment 120, wherein the zoledronic acidin the disodium salt form provides an enhancement to bioavailability, ascompared to zoledronic acid in the diacid form, which adds to anyenhancement to bioavailability provided by any bioavailability-enhancingagents in the dosage form.

Embodiment 122 The method of embodiment 120, wherein the dosage form issubstantially free of bioavailability-enhancing agents.

Embodiment 123 The method of embodiment 120, wherein the zoledronic acidin the disodium salt form is administered to a mammal in an amount thatprovides an area under the plasma concentration curve of zoledronic acidof about 4 ng·h/mL to about 2000 ng·h/mL to the mammal each time thezoledronic acid in the disodium salt is administered.

Embodiment 124 The method of embodiment 123, wherein the zoledronic acidin the disodium salt form is administered at an interval of about 3 toabout 4 weeks in an amount that provides an area under the plasmaconcentration curve of zoledronic acid of about 100 ng·h/mL to about2000 ng·h/mL to the mammal each time the zoledronic acid in the disodiumsalt form is administered.

Embodiment 125 The method of embodiment 123, wherein the zoledronic acidin the disodium salt form is administered weekly, or 3 to 5 times in amonth, in an amount that provides an area under the plasma concentrationcurve of zoledronic acid of about 20 ng·h/mL to about 700 ng·h/mL to themammal each time the zoledronic acid in the disodium salt form isadministered.

Embodiment 126 The method of embodiment 123, wherein the zoledronic acidin the disodium salt form is administered daily in an amount thatprovides an area under the plasma concentration curve of zoledronic acidof about 4 ng·h/mL to about 100 ng·h/mL to the mammal each time thezoledronic acid in the disodium salt form is administered.

Embodiment 127 The method of embodiment 120, wherein the dosage form isa solid.

Embodiment 128 The method of embodiment 120, 121, 122, 123, 124, 125,126, or 127, wherein the bioavailability of zoledronic acid is improvedby at least about 20% as compared to administration of zoledronic acidin the diacid form.

Embodiment 129 The method of embodiment 120, 121, 122, 123, 124, 125,126, 127, or 128, further comprising administering, on a molar basis,less of the zoledronic acid in the disodium salt form than would beadministered of zoledronic acid in the diacid form in order to achievethe same plasma levels of zoledronic acid.

Embodiment 130 The method of embodiment 129, wherein at least about 10mole % less of the disodium salt form is administered as compared theamount of zoledronic acid in the diacid form that would be administeredin order to achieve the same plasma levels of zoledronic acid.

Embodiment 131 The method of embodiment 129, wherein the disodium saltform is administered in an amount, on a molar basis, that has a value ofabout 0.8n_(d) to about 1.2n_(d), wherein:n _(d)=(b _(a) /b _(d))(n _(a))wherein b_(a) is the bioavailability of the diacid form, b_(d) is thebioavailability of the disodium salt form, and n_(a) is the number ofmoles of zoledronic acid in the diacid form that would be administeredin order to achieve the same plasma levels of zoledronic acid.

Embodiment 132 The method of embodiment 131, wherein the disodium saltis administered in an amount that has a value of about n_(d).

Embodiment 133 The method of any of embodiments 120-132, wherein thezoledronic acid is used to treat an inflammatory condition.

Embodiment 134 The method of embodiment 133, wherein the zoledronic acidis used to treat arthritis.

Embodiment 135 The method of embodiment 133, wherein the zoledronic acidis used to treat complex regional pain syndrome.

Embodiment 136 The method of any of embodiments 1-39, 62-77, and120-135, wherein:

-   -   a first oral dosage form is administered; and    -   a second oral dosage form is administered;    -   wherein, with respect to the first oral dosage form, the second        oral dosage form is administered at 10×T_(max) or greater,        wherein T_(max) is the time of maximum plasma concentration for        the first oral dosage form.

Embodiment 137 A dosage form comprising zoledronic acid in the disodiumsalt form, wherein the bioavailability, in a mammal, of zoledronic acidin the disodium salt form is greater than the bioavailability ofzoledronic acid in the diacid form would be in the same dosage form.

Embodiment 138 A dosage form comprising zoledronic acid in the disodiumsalt form, wherein the dosage form contains an amount of zoledronic acidin the disodium salt form that provides an area under the plasmaconcentration curve of zoledronic acid of about 4 ng·h/mL to about 2000ng·h/mL to a human being to which the dosage form is administered.

Embodiment 139 The dosage form of embodiment 138, wherein the dosageform contains an amount of zoledronic acid in the disodium salt formthat provides an area under the plasma concentration curve of zoledronicacid of about 100 ng·h/mL to about 2000 ng·h/mL to a human being towhich the dosage form is administered.

Embodiment 140 The dosage form of embodiment 138, wherein the dosageform contains an amount of zoledronic acid in the disodium salt formthat provides an area under the plasma concentration curve of zoledronicacid of about 20 ng·h/mL to about 700 ng·h/mL to a human being to whichthe dosage form is administered.

Embodiment 141 The dosage form of embodiment 138, wherein the dosageform contains an amount of zoledronic acid in the disodium salt formthat provides an area under the plasma concentration curve of zoledronicacid of about 4 ng·h/mL to about 100 ng·h/mL to a human being to whichthe dosage form is administered.

Embodiment 142 A dosage form comprising zoledronic acid in the disodiumsalt form,

-   -   wherein the disodium salt form is present in a lower molar        amount than would be present if the zoledronic acid were in the        diacid form; and    -   wherein the zoledronic acid in the disodium salt form has an        improved bioavailability as compared to the zoledronic acid in        the diacid form to the extent that the lower molar amount of the        disodium salt in the dosage form does not reduce the amount of        zoledronic acid delivered to the plasma of a mammal.

Embodiment 143 The dosage form of embodiment 137, 138, 139, 140, 141, or142, wherein the dosage form is a solid.

Embodiment 144 The dosage form of embodiment 142 or 143, wherein thebioavailability of zoledronic acid in the disodium salt form is improvedby at least about 10% as compared to an otherwise identical dosage formcontaining zoledronic acid in the diacid form.

Embodiment 145 The dosage form of embodiment 142, 143, or 144,containing at least about 20 mole % less of the disodium salt form ascompared to the amount of the zoledronic acid in the diacid form thatwould be present if the zoledronic acid were in the diacid form.

Embodiment 146 The dosage form of embodiment 142, wherein the disodiumsalt form is present in an amount, on a molar basis, that has a value ofabout 0.9 nd to about 1.1 nd, wherein:n _(d)=(b _(a) /b _(d))(n _(a))

-   -   wherein b_(a) is the bioavailability of the diacid form, b_(d)        is the bioavailability of the disodium salt form, and n_(a) is        the number of moles of the diacid form that would be present if        the zoledronic acid were in the diacid form.

Embodiment 147 The dosage form of embodiment 146, wherein the disodiumsalt is administered in an amount that has a value of about n_(d).

Embodiment 148 The method of any of embodiments 1-39, 62-77, and120-136, wherein:

-   -   only a single oral dosage form is administered; or    -   a first oral dosage form is administered, and a second oral        dosage form is administered after the first oral dosage form,        wherein the second oral dosage form is administered before the        maximum pain relieving effect of the first oral dosage form is        achieved, or the second oral dosage form is administered before        an observable pain relieving effect is achieved.

Embodiment 149 The method of embodiment 148, wherein the second oraldosage form is administered before an observable pain relieving effectis achieved.

Embodiment 150 The method of any of embodiments 1-39, 62-77, and120-132, wherein a first dosage form is administered, followed byadministration of a second dosage form, wherein the second dosage formis administered after the maximum pain relieving effect of the firstoral dosage form is achieved, and the second oral dosage form isadministered while a pain relieving effect from the first oral dosageform is observable.

Embodiment 151 The method of embodiment 148, 149, or 150, wherein thesecond oral dosage form is administered about 24 hours to about 28 daysafter the first oral dosage form is administered.

Embodiment 152 The method of any of embodiments 20-39, wherein the humanbeing is about 30 years old to about 75 years old.

Embodiment 153 The method of any of embodiments 20-39, wherein the humanbeing is about 1 year old to about 16 years old.

Embodiment 154 The method of any of embodiments 20-39, wherein the humanbeing is about 80 years old to about 95 years old.

Embodiment 155 The method of any of embodiments 20-39, wherein the humanbeing has suffered from the arthritis for at least 2 months.

Embodiment 156 The method of any of embodiments 20-39, wherein thearthritis affects, a knee, an elbow, a wrist, a shoulder, or a hip.

Embodiment 157 The method of any of embodiments 1-44, 62-133, and144-156, wherein the mammal or human being to which the zoledronic acidis administered does not eat food or drink beverage for at least 1 hourbefore the zoledronic acid is administered.

Embodiment 158 The method of embodiment 157, wherein the mammal or humanbeing to which the zoledronic acid is administered does not eat food ordrink beverage for at least 2 hours before the zoledronic acid isadministered.

Embodiment 159 The method of embodiment 158, wherein the mammal or humanbeing to which the zoledronic acid is administered does not eat food ordrink beverage for at least 4 hours before the zoledronic acid isadministered.

Embodiment 160 The method of embodiment 159, wherein the mammal or humanbeing to which the zoledronic acid is administered does not eat food ordrink beverage for at least 6 hours before the zoledronic acid isadministered.

Embodiment 161 The method of any of embodiments 157-160, wherein themammal or human being to which the zoledronic acid is administered doesnot eat food or drink beverage for at least 30 minutes after thezoledronic acid is administered.

Embodiment 162 The method of embodiment 161, wherein the mammal or humanbeing to which the zoledronic acid is administered does not eat food ordrink beverage for at least 1 hour after the zoledronic acid isadministered.

Embodiment 163 The method of embodiment 161, where in the mammal orhuman being to which the zoledronic acid is administered does not eatfood or drink beverage for at least 2 hours after the zoledronic acid isadministered.

Embodiment 164 The method, dosage form, or product, of any precedingembodiment, wherein the zoledronic acid in the oral dosage form has a 24hour sustained plasma level factor of about 1 or higher.

Embodiment 165 The method, dosage form, or product, of any precedingembodiment, wherein the zoledronic acid in the oral dosage form has a 24hour sustained plasma level factor that is higher than that ofintravenously administered zoledronic acid.

Embodiment 166 The method, dosage form, or product, of any precedingembodiment, wherein the oral dosage form is a solid that has a hardnessof about 5 kPa to about 20 kPa.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodin all instances as indicating both the exact values as shown and asbeing modified by the term “about.” Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary depending upon thedesired properties sought to be obtained. At the very least, and not asan attempt to limit the application of the doctrine of equivalents tothe scope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorexpects skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise thanspecifically described herein. Accordingly, the claims include allmodifications and equivalents of the subject matter recited in theclaims as permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof iscontemplated unless otherwise indicated herein or otherwise clearlycontradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

The invention claimed is:
 1. A method of safely treating low back painby an oral route comprising orally administering a safe and effectiveamount of zoledronic acid to a human being suffering from low back pain,wherein the human being receives about 80 mg to about 600 mg of thezoledronic acid within a period of two months, wherein the zoledronicacid is orally administered as 3 to 9 divided doses that areadministered no more often than once a week, and wherein the human beingexperiences pain relief that lasts for a duration of at least 48 hours.2. The method of claim 1, wherein the human being receives about 80 mgto about 300 mg of the zoledronic acid in a period of one month or less.3. The method of claim 1, wherein the human being to which thezoledronic acid is administered does not eat food or drink beverage forat least 30 minutes after the zoledronic acid is orally administered. 4.The method of claim 2, wherein the human being to which the zoledronicacid is administered does not eat food or drink beverage for at least 30minutes after the zoledronic acid is orally administered.
 5. The methodof claim 1, wherein the human being to which the zoledronic acid isadministered does not eat food or drink beverage for at least 1 hourbefore the zoledronic acid is orally administered.
 6. The method ofclaim 5, wherein the zoledronic acid is administered in an oral dosageform that is at least 10% zoledronic acid by weight.
 7. The method ofclaim 1, wherein the zoledronic acid is orally administered for 1 to 2months.
 8. The method of claim 1, wherein the zoledronic acid is orallyadministered weekly.
 9. The method of claim 5, wherein the zoledronicacid is orally administered weekly for 1 to 2 months.
 10. The method ofclaim 9, wherein about 10 mg to about 100mg of the zoledronic acid isorally administered weekly.
 11. The method of claim 10, wherein thezoledronic acid is administered in an oral dosage form that is at least10% zoledronic acid by weight.
 12. The method of claim 9, wherein about40 mg to about 50 mg of the zoledronic acid is orally administeredweekly.
 13. The method of claim 12, wherein the zoledronic acid isadministered in an oral dosage form that is at least 10% zoledronic acidby weight.
 14. The method of claim 9, wherein about 50 mg of thezoledronic acid is orally administered weekly.
 15. The method of claim14, wherein the zoledronic acid is administered in an oral dosage formthat is at least 10% zoledronic acid by weight.
 16. The method of claim9, wherein about 50 mg to about 100 mg of the zoledronic acid is orallyadministered weekly.
 17. The method of claim 16, wherein the zoledronicacid is administered in an oral dosage form that is at least 10%zoledronic acid by weight.
 18. The method of claim 1, wherein thezoledronic acid is orally administered weekly for 1 to 2 months.
 19. Themethod of claim 1, wherein about 50 mg of the zoledronic acid isadministered weekly for six consecutive weeks.
 20. The method of claim1, wherein the zoledronic acid is orally administered as 3 to 6 divideddoses.
 21. The method of claim 1, wherein the zoledronic acid is orallyadministered as 4 to 9 divided doses.
 22. The method of claim 1, whereinthe zoledronic acid is administered in a solid dosage form having ahardness of about 5 kPa to about 20 kPa.
 23. The method of claim 1,wherein the human being remains upright or sits upright for at least 30minutes after the zoledronic acid is orally administered.
 24. The methodof claim 1, wherein the human being remains upright or sits upright forat least 1 hour after the zoledronic acid is orally administered. 25.The method of claim 1, wherein the human being is fasted for at least 2hours before the zoledronic acid is orally administered.
 26. The methodof claim 1, wherein the human being is fasted for at least 4 hoursbefore the zoledronic acid is orally administered.
 27. The method ofclaim 1, wherein the human being is fasted for at least 6 hours beforethe zoledronic acid is orally administered.
 28. The method of claim 1,wherein the human being is fasted for at least 8 hours before thezoledronic acid is orally administered.
 29. The method of claim 1,wherein the human being is fasted for at least 10 hours before thezoledronic acid is orally administered.
 30. The method of claim 1,wherein the human being is fasted for at least 12 hours before thezoledronic acid is orally administered.